title: Hepatitis B virus limits response of human hepatocytes to interferon-α in chimeric mice.
abstract: OBJECTIVE
  Interferon (IFN)-α therapy is not effective for most patients with chronic hepatitis B virus (HBV) infection for reasons that are not clear. We investigated whether HBV infection reduced IFN-α-mediated induction of antiviral defense mechanisms in human hepatocytes.
  
  
  METHODS
  Human hepatocytes were injected into severe combined immune-deficient mice (SCID/beige) that expressed transgenic urokinase plasminogen activator under control of the albumin promoter. Some mice were infected with HBV; infected and uninfected mice were given injections of human IFN-α. Changes in viral DNA and expression of human interferon-stimulated genes (ISGs) were measured by real-time polymerase chain reaction, using human-specific primers, and by immunohistochemistry.
  
  
  RESULTS
  Median HBV viremia (0.8log) and intrahepatic loads of HBV RNA decreased 3-fold by 8 or 12 hours after each injection of IFN-α, but increased within 24 hours. IFN-α activated expression of human ISGs and nuclear translocation of signal transducers and activators of transcription-1 (STAT1) in human hepatocytes that repopulated the livers of uninfected mice. Although baseline levels of human ISGs were slightly increased in HBV-infected mice, compared with uninfected mice, IFN-α failed to increase expression of the ISGs OAS-1, MxA, MyD88, and TAP-1 (which regulates antigen presentation) in HBV-infected mice. IFN-α did not induce nuclear translocation of STAT1 in HBV-infected human hepatocytes. Administration of the nucleoside analogue entecavir (for 20 days) suppressed HBV replication but did not restore responsiveness to IFN-α.
  
  
  CONCLUSIONS
  HBV prevents induction of IFN-α signaling by inhibiting nuclear translocation of STAT1; this can interfere with transcription of ISGs in human hepatocytes. These effects of HBV might contribute to the limited effectiveness of endogenous and therapeutic IFN-α in patients and promote viral persistence.
authors.affiliation: Department of Internal Medicine, University Medical Hospital Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Lütgehetmann
authors.forename: Till
authors.initials: T
authors.lastname: Bornscheuer
authors.forename: Tassilo
authors.initials: T
authors.lastname: Volz
authors.forename: Lena
authors.initials: L
authors.lastname: Allweiss
authors.forename: Jan-Hendrick
authors.initials: JH
authors.lastname: Bockmann
authors.forename: Joerg M
authors.initials: JM
authors.lastname: Pollok
authors.forename: Ansgar W
authors.initials: AW
authors.lastname: Lohse
authors.forename: Joerg
authors.initials: J
authors.lastname: Petersen
authors.forename: Maura
authors.initials: M
authors.lastname: Dandri
mesh_terms: D021581:Active Transport, Cell Nucleus; D000418:Albumins / Q000235:genetics; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage*; D004279:DNA, Viral / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006509:Hepatitis B / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000637:transplantation*; D006801:Humans; D007150:Immunohistochemistry; D016898:Interferon-alpha / Q000008:administration & dosage*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D012367:RNA, Viral / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D018183:Transplantation Chimera; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics
chemical_list: D000418:Albumins; D000998:Antiviral Agents; D004279:DNA, Viral; D016898:Interferon-alpha; D012367:RNA, Viral; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C413685:entecavir; D006147:Guanine; D014568:Urokinase-Type Plasminogen Activator